摘要:

The use of corticosteroids in patients with septic shock has been recently revisited and the use of low dose corticosteroids led to very promising results, particularly in patients with corticosteroid insufficiency. We review the different mechanisms that can account for their beneficial effects in patients. Glucocorticoids display a wide spectrum of anti-inflammatory properties that have been identified inin vitroandin vivoexperimental models (e.g., inhibition of production of pro-inflammatory cytokines, free radicals, prostaglandins and inhibition of chemotaxis, and adhesion molecule expressions.) In addition, glucocorticoids have profound effects on the cardiovascular system (e.g., increasing mean blood pressure, increasing pressor sensitivity, and therefore decreasing the duration of use of catecholamines during septic shock.) Through these anti-inflammatory and cardiovascular effects, low doses of glucorticoids may improve septic shock survival.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We evaluated neutrophil activation by measuring its phagocytic ability and oxidative burst activity in 16 patients with sepsis and 16 healthy volunteers. We also focused on neutrophil apoptosis as a regulatory mechanism of the inflammatory response. Neutrophil phagocytosis was evaluated by the detection of propidium iodide (PI)-labeledStaphylococcus aureusadded to whole blood. Reactive oxygen species (ROS) formation was quantified by measuring the oxidation of 2´,7´ dichlorofluorescein diacetate (DCFH-DA) at baseline and after cell stimulation with phorbol myristate acetate (PMA), and bacterial cells (killedS. aureus) or products (lipopolysaccharide [LPS] andN-formyl-methionyl-leucyl-phenylalanine [FMLP]). Apoptosis was assessed in neutrophils stained with annexin V and PI. Neutrophil phagocytic ability was increased in patients with sepsis compared with healthy controls (median geometric mean fluorescence intensity [GMFI] was 101.9 and 54.7, respectively;P= 0.05). ROS formation was enhanced in patients with sepsis compared with healthy volunteers at baseline (median GMFI 275.6 and 52.1, respectively;P< 0.001), and after stimulation withS. aureus(median GMFI 2395.8 and 454.9, respectively;P< 0.001), PMA (median GMFI 1120.6 and 307.5, respectively;P= 0.003), FMLP (median GMFI 792.4 and 123.2, respectively;P< 0.001), and LPS (median GMFI 624.8 and 144.8, respectively;P< 0.001). Early neutrophil apoptosis was increased in patients with sepsis compared with healthy volunteers (median 11.3% and 9.1%, respectively;P= 0.03). These data demonstrate that neutrophil function is enhanced in patients with sepsis. Additionally, circulating neutrophils from patients with sepsis presented with increased early apoptosis, which may be consequence of a regulatory mechanism of the inflammatory response.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The balance between proinflammatory and anti-inflammatory processes is of key importance in the reaction of the body to infection, injury, and surgical trauma. Drugs commonly used in anesthesia and intensive care may modulate immunological reactions by influencing intercellular communication through modification of cytokine response and fluctuation of peripheral immune cells such as natural killer (NK) cells, B cells, and T lymphocyte subpopulations (CD4+and CD8+cells). To examine the effects of general anesthesia with the hypnotic agent propofol and the opioid fentanyl, 30 patients undergoing minor elective orthopedic surgery were studied before and 20 min after application of the anesthetic drugs, but before the start of surgery. We found a significant enhancement of TNF-&agr; and IL-1&bgr; release in lipopolysaccharide (LPS)-stimulated whole blood cultures after induction of anesthesia. Similar results were observed with interferon-&ggr; (IFN-&ggr;) in cultures stimulated with phytohemagglutinin (PHA). Conversely, synthesis of the anti-inflammatory cytokine interleukin 10 (IL-10) decreased significantly in LPS-stimulated cultures. During general anesthesia, we found a decrease of circulating lymphocytes, characterized by a significant increase in the percentage of T lymphocytes in favor of CD4+cells, increased B lymphocytes, and a significant decrease of NK cells. These data suggest that anesthesia with propofol and fentanyl promotes proinflammatory immune responses and influences peripheral lymphocyte composition in patients, which may subsequently affect pathophysiological processes during opioid-based anesthesia.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Genetic variations contribute to differences in the inflammatory response and are markers for disease risk and outcomes. We studied three single-nucleotide polymorphisms (−597 G→A, −572 G→C, and −174 G→C) in the IL-6 promoter to determine associations withex vivoLPS-stimulated IL-6 production by leukocytes. We also measured nuclear protein binding to synthetic oligonucleotides representing the −174 polymorphic region, located in proximity to important transcription factor motifs. We determined genotypes at three sites in the IL-6 promoter by pyrosequencing of genomic DNA obtained from 49 healthy control subjects. To determine molecular haplotypes, cloned DNA fragments from heterozygous subjects were sequenced. IL-6 release by whole blood leukocytes was measured after 24 h ofex vivoLPS stimulation. We compared IL-6 concentrations between haplotypes using Kruskall-Wallis and adjusted for covariates by analysis of covariance. Electromobility gel shift assay was carried out by the incubation of nuclear proteins from cultured human mononuclear cells with oligonucleotides representing the alternate −174 alleles. The amount of nuclear protein binding was quantified by densitometry, which was compared using analysis of variance. Genotype and sequence analysis of genomic and cloned DNA characterized three haplotypes.Ex vivoIL-6 production was greatest in individuals who were homozygous for the haplotype containing guanine at −597 and −174. IL-6 production was least for individuals homozygous for the haplotype containing adenine at −597 and cytosine at −174. Nuclear protein bound more avidly to guanine-containing oligonucleotides representing the −174 position than to oligonucleotides containing cytosine at that position. The IL-6 promoter haplotype influencesex vivoIL-6 response to endotoxin. This effect may be due to a functional effect of the –174 G→C polymorphism.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Toll-like receptors (TLR) play a pivotal role in the innate immune response, and the expression levels of these receptors may reflect the sensitivity of immune cells to infections. The binding of lipopolysaccharide (LPS) to TLR-4 triggers human monocytes to produce cytokines, which play a dominant role in the inflammatory response, as can be observed during sepsis and after polytrauma. Here, we evaluated TLR-4 expression of isolated monocytes in the presence of tumor necrosis factor (TNF)-&agr;, interleukin (IL) 6, IL-8, and IL-10, and we investigated cellular activation of this treatment. TNF-&agr; significantly down-regulated TLR-4 mRNA expression after 6 h (100% vs. 38.5% ± 4%;P< 0.05). This down-regulation was followed by a dose- and time-dependent diminished expression of TLR-4 surface protein (100% vs. 8.0% ± 5%;P< 0.01). Forty-eight hours after TNF-&agr; treatment, a reduced nuclear factor (NF)-&kgr;B translocation and a diminished IL-6 secretion after LPS stimulation were found (100% vs. 42.0% ± 23%;P< 0.05). In contrast, IL-6 incubation upregulated TLR-4 cell surface protein (100% vs. 165.8% ± 24%;P< 0.05) and increased the ability to activate NF-&kgr;B and AP-1 after LPS stimulation. Stimulation with IL-8 or IL-10 had no significant effects. We conclude that not only LPS but also TNF-&agr; and IL-6 have the potency to regulate the immune response via TLR-4. Down-regulation of TLR-4 by TNF-&agr; is associated with LPS hyporeactivity for NF-&kgr;B formation, whereas upregulation of TLR-4 via IL-6 can increase the responsiveness of mononuclear phagocytes.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

In the present study, we used 5-lipoxygenase (5-LO) knockout (KO) mice to evaluate the possible role of 5-LO on the pathogenesis of splanchnic artery occlusion (SAO) shock. SAO shock was induced in mice by clamping both the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by release of the clamp (reperfusion). At 120 min after reperfusion, animals were sacrificed for histological examination and biochemical studies. There was a marked increase in the lipid peroxidation in the ileum as well as in the lung of the SAO-shocked 5-LO wild-type (WT) mice after reperfusion. The absence of 5-LO did not reduce the lipid peroxidation in the intestine or the lung. SAO-shocked WT mice developed a significant increase of tissue (ileum and lung) myeloperoxidase activity and marked histological injury. SAO shock was also associated with a significant mortality (50% survival at 5 h after reperfusion). Reperfused ileum and lung tissue sections from SAO-shocked WT mice showed positive staining for P-selectin, ICAM-1, and E-selectin that was mainly localized in the vascular endothelial cells. The intensity and degree of P-selectin, E-selectin, and ICAM-1 were markedly reduced in tissue section from SAO-shocked 5-LOKO mice. SAO-shocked 5-LOKO mice showed also a significant reduction of the neutrophils infiltration into the reperfused intestine as well as in the lung as evidenced by reduced myeloperoxidase activity, an improved histological status of the reperfused tissues, and an improved survival. Taken together, our results clearly demonstrate that 5-LO plays an important role in ischemia and reperfusion injury and put forward the hypothesis that inhibition of 5-LO may represent a novel and possible strategy in the treatment of ischemia and reperfusion injury. Part of this effect may be due to inhibition of the expression of adhesion molecules and subsequent reduction of neutrophil-mediated cellular injury.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Ethanol (EtOH) blunts the respiratory and metabolic compensation during hemorrhage, resulting in a more severe lactic acidemia. We hypothesized that lactated Ringer's (LR) resuscitation may exacerbate this lactic acidemia. Male guinea pigs were implanted with arterial and venous catheters. Two days after catheter placement, conscious animals were injected intraperitoneally with 1 g/kg EtOH, 0.3 g/kg EtOH, or an equal volume of water 30 min before hemorrhage (60% of estimated blood volume). After 30 min of hemorrhagic shock, animals were resuscitated with isotonic saline (S) or LR at 1 mL/min (three times shed blood volume). Mean arterial blood pressure (MABP) was not affected by pretreatment with either dose of EtOH, but was significantly decreased by hemorrhage in all groups. Both S and LR resuscitation slightly increased MABP, but neither restored it to prehemorrhage values. Blood lactate levels increased in all groups during hemorrhage and remained elevated for 3 h in animals pretreated with 1 g/kg EtOH. In the group pretreated with 0.3 g/kg EtOH, pH decreased during shock but returned to prehemorrhage levels during the resuscitation period. Resuscitation with S returned pH to prehemorrhage values in animals pretreated with 1.0 g/kg EtOH. Resuscitation with LR did not exacerbate, but did prolong, the lactic acidemia after shock in animals pretreated with 1.0 g/kg EtOH. Administration of additional lactate during intoxication and hypovolemia for hemodynamic stabilization before blood transfusion may exacerbate a metabolic stress.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

D-lactate is produced by indigenous bacteria in the gastrointestinal tract. Mammals do not have the enzyme systems to metabolize D-lactate rapidly. The present study was designed to determine the kinetics of circulating D-lactate levels and to examine whether the severity of shock affects circulating D-lactate levels in rats subjected to hemorrhagic/traumatic shock. Anesthetized rats underwent midline laparotomy (duration 30 min) and were bled to 30–35 mmHg mean arterial pressure (MAP). After the onset of decompensation, MAP was either increased to 40–45 mmHg immediately by administration of Ringer's solution (moderate shock) or after 40% of shed blood volume had been re-infused as Ringer's solution (severe shock). MAP was then maintained at 40–45 mmHg for 40 min by further administration of Ringer's solution (inadequate resuscitation). Subsequently, adequate resuscitation was performed for 60 min with shed blood and additional Ringer's solution. Metabolic acidosis was significantly more pronounced in severe than in moderate hemorrhagic/traumatic shock. Plasma D-lactate levels were already significantly increased at the end of severe hemorrhagic/traumatic shock and remained high during inadequate resuscitation. D-lactate levels were significantly higher after severe than after moderate shock. Endotoxin levels did not correlate with shock severity. Damage to the intestinal mucosa was more profound in severe shock than in moderate shock. Our data suggest that hemorrhagic/traumatic shock is associated with mucosal damage and increased plasma D-lactate levels. The severity of shock affects D-lactate concentrations in plasma. Plasma D-lactate may be a useful marker of intestinal injury after hemorrhagic/traumatic shock.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Coliforms are the members of the indigenous gut flora that most often translocate to mesenteric lymph nodes. Very few strains ofEscherichia colifound in cecal contents of rats are able to translocate. The present study investigated the role of the composition of the gut flora for the occurrence of bacterial translocation. Two strains ofE. coli(KI-C1 and KI-C2), previously shown to translocate in rats subjected to stress, were given by oral inoculation to rats lacking these strains. A biochemical fingerprinting method was used to identify bacteria in cecal contents, on cecal epithelium, and in mesenteric lymph nodes. In a challenge study, the inoculatedE. colistrains were shown to colonize the rats and persist for up to 75 days in cecum. Subsequently, one group was starved for 24 h and a second group was subjected to experimental hemorrhage and then starved for 24 h before sampling for bacteriological analyses from blood, cecum, and mesenteric lymph nodes. Two parallel groups of rats served as controls and were not inoculated but otherwise received the same treatment before sampling. In the inoculated group, starved for 24 h, seven out of 11 rats showed translocation, whereas in the noninoculated group one of 11 rats showed translocation (P< 0.05). In groups subjected to hemorrhage and then starved for 24 h, 15/22 rats in the inoculated and 5/20 rats in the noninoculated group showed translocation (P< 0.01). These findings show that orally inoculated KI-C1 and KI-C2 strains can colonize the gut and can substantially increase bacterial translocation in rats subjected to mild and severe stress. The composition of the gut flora seems to be an underestimated factor in the pathophysiology of bacterial translocation.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Staphylococcal enterotoxin B (SEB) is an important member of the superantigen family, which exerts a number of pathological effects in the human, as well as susceptible animals. The present study was conducted to observe the time course and tissue distribution of SEB in postburnStaphylococcus aureusinfection; meanwhile, the relationship between SEB and multiple organ dysfunction was also studied. Eighty-six male Wistar rats were randomly divided into four groups as follows: normal control group (n = 10); scald control group (n = 10); postburn sepsis group (n = 50) in which rats inflicted with 20% total body surface area (TBSA) III° scald followed by SEB-producingS. aureuschallenge were further divided into 0.5-, 2-, 6-, 12-, and 24-h subgroups, with 10 rats in each subgroup; and SEB monoclonal antibody (MAb) treatment group (n = 16) in which a dose of 4 mg/kg SEB MAb was given intravenously just beforeS. aureuschallenge, and the rats were further divided into 2- and 6-h subgroups. It was found that after thermal injury combined withS. aureusinfection, SEB was widely distributed to the liver, kidneys, lungs, and heart, exacerbating the pathophysiology of multiple organ dysfunction induced by postburn sepsis. At the same time, the gene and protein expressions of tumor necrosis factor-&agr; (TNF-&agr;) and interferon-&ggr; (IFN-&ggr;) were also markedly upregulated in various tissues. Early treatment with SEB-specific MAb—MAb2D1—could markedly decrease SEB levels in plasma as well as in various tissues, and could significantly reduce the 6-h mortality rate (17.64% [3/17] vs. 55.6% [20/36],P= 0.02). These data suggested that neutralization of SEB is effective in amelioratingS. aureussepsis and subsequent multiple organ damage, which might be attributed to its inhibitory effect on inflammatory mediator formation.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID